Clinical consequences of androgen receptor malfunction

The androgen receptor (AR), the mediator of the effects of the male sex hormones testosterone and dihydrotestosterone, plays a crucial role in development of male sex and in the function of male sexual organs. Pathological alterations of AR structure and function are a major cause of androgen insensitivity in male pseudohermaphroditism and the accompanying deformations of genital organs, or result in spinal and bulbar muscular atrophy (SBMA). In addition, AR alterations that generate a hyperreactive receptor contribute to the development of resistance to hormone ablation therapy in prostate cancer. AR mutations found in patients with male pseudohermaphroditism usually are missens mutations that result in exchange of a single amino acid and cause complete or partial loss of function. The molecular change underlaying spinal and bulbar muscular atrophy is an extension of a poly-CAG repeat in the AR gene. The affected receptor tends to form aggregates, which damage motoneurons. Androgen ablation therapy puts prostate tumor cells under selection pressure that finally results in development of a hyperreactive androgen receptor that is activated under the conditions of therapy.